Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells.

Autor:	Schreck C; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Istvánffy R; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Ziegenhain C; Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany., Sippenauer T; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Ruf F; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Henkel L; Department of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany., Gärtner F; Department of Internal Medicine I, Ludwig-Maximilian-Universität, 81377 Munich, Germany., Vieth B; Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany., Florian MC; Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany., Mende N; Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, TU Dresden, 01309 Dresden, Germany., Taubenberger A; Biotechnology Center TU Dresden, 01307 Dresden, Germany., Prendergast Á; German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany., Wagner A; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Pagel C; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Grziwok S; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Götze KS; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.; German Cancer Consortium, DKFZ, 69120 Heidelberg, Germany., Guck J; Biotechnology Center TU Dresden, 01307 Dresden, Germany., Dean DC; Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202., Massberg S; Department of Internal Medicine I, Ludwig-Maximilian-Universität, 81377 Munich, Germany., Essers M; German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany., Waskow C; Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, TU Dresden, 01309 Dresden, Germany., Geiger H; Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany., Schiemann M; Department of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany., Peschel C; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.; German Cancer Consortium, DKFZ, 69120 Heidelberg, Germany., Enard W; Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany., Oostendorp RA; Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany robert.oostendorp@tum.de.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2017 Jan; Vol. 214 (1), pp. 165-181. Date of Electronic Publication: 2016 Dec 20.
DOI:	10.1084/jem.20151414
Abstrakt:	Here, we show that the Wnt5a-haploinsufficient niche regenerates dysfunctional HSCs, which do not successfully engraft in secondary recipients. RNA sequencing of the regenerated donor Lin - SCA-1 + KIT + (LSK) cells shows dysregulated expression of ZEB1-associated genes involved in the small GTPase-dependent actin polymerization pathway. Misexpression of DOCK2, WAVE2, and activation of CDC42 results in apolar F-actin localization, leading to defects in adhesion, migration and homing of HSCs regenerated in a Wnt5a-haploinsufficient microenvironment. Moreover, these cells show increased differentiation in vitro, with rapid loss of HSC-enriched LSK cells. Our study further shows that the Wnt5a-haploinsufficient environment similarly affects BCR-ABL p185 leukemia-initiating cells, which fail to generate leukemia in 42% of the studied recipients, or to transfer leukemia to secondary hosts. Thus, we show that WNT5A in the bone marrow niche is required to regenerate HSCs and leukemic cells with functional ability to rearrange the actin cytoskeleton and engraft successfully. (© 2017 Schreck et al.)
Databáze:	MEDLINE
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